After running 4th edition D&D for the first time last Wed for D&D Encounters, I have to say it's still recognizable as derived from 3rd edition Dungeons & Dragons. Combat still works basically the same, initiative still works the same, there are still the same basic character classes and c but I could recognize the game and it still runs very similar to 1st, 2nd, and 3rd editions.
The major difference I see is that the power level has been significantly ramped up for beginning characters, especially for mages and clerics. Their starting spell numbers have significantly ramped up over previous editions. The priest character in the game has a couple of at will spells that could cast every round, a far cry from "I have magic missile and read magic." A first level spellcaster doesn't have to cower at the back of the party once they use their lone spell, they can keep mixing it up with the rest of the group.
Healing surges mean the party cleric doesn't have to load up on healing spells, giving up all offensive spells to serve as the party's first aid kit. On the one hand, this lets the cleric get more involved in all askpects of the adventure. On the other hand, the other party members are much less concerned about protesting the priest. No more cries of "Cleric!"